Emerging Osteoarthritis Therapies

There is hope for horses affected by osteoarthritis as researchers continue to explore and develop disease-modifying techniques.

Most horse owners are already aware that osteoarthritis (OA) is one of the most important health-related problems for horses. The condition limits a horse's athleticism and can, like any chronically painful condition, negatively impact a horse's quality of life. Researchers estimate that this disease is the single most important cause of lameness in horses and that 60% of lameness problems are related to OA. Millions of horses are affected by OA, and costs associated with diagnosing and treating it can be as high as $15,000 per horse per year (TheHorse.com/14841).

While there is no cure for OA, treatment options abound. Two types or classes of medical treatments for OA-affected horses exist. One is called "symptomatic" and the other type is "disease-modifying." Symptomatic treatments for OA reduce clinical signs (e.g., heat, pain, lameness, swelling), helping the horse feel more comfortable and move easier. These symptomatic treatments, such as the anti-inflammatory drug phenylbutazone (Bute), however, do not stop the disease from progressing.

How Osteoarthritis Develops

Osteoarthritis (OA) is a painful condition primarily characterized by the progressive destruction of articular cartilage. Articular cartilage lines the ends of long bones where they joint together and transfer load during weight bearing. Without the cartilage, the bones are not "cushioned" during weight bearing, resulting in pain and inflammation during locomotion. A number of factors can cause or contribute to the degradation and destruction of articular cartilage. These include fracture within the joint (e.g., chip fracture); subchondral bone disease (e.g., osteochondritis dissecans); or inflammatory conditions such as synovitis or capsulitis, which are inflammation of the inner lining of the joint (the synovium) or the joint capsule, respectively. Regardless of the inciting factor, once the joint becomes inflamed, the articular cartilage is at risk. Various pro-inflammatory molecules (cytokines) are released into the joint, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα). Metalloproteinases, enzymes that breakdown articular cartilage, are also produced and released in the joint. Together, these molecules cause the progressive deterioration of the articular cartilage and subchondral bone (the bone lying directly under the articular cartilage).

--Stacey Oke, MSc

"The symptomatic treatment options, such as oral or intravenous administration of phenylbutazone or the intra-articular administration of the corticosteroid called methylprednisolone acetate, decrease inflammation, but they are unable to completely control the discomfort caused by OA," explains Wayne McIlwraith, BVSc, PhD, DSc, FRCVS, Dipl. ACVS, director of the Orthopaedic Research Center at Colorado State University.

Instead, "disease-modifying" treatments are needed to slow, stop, or even reverse the degenerative process.

Unfortunately, not all of these disease-modifying therapies are currently available to horse owners. Gene therapy, for instance, remains in the experimental stages, although according to McIlwraith, "the preliminary results are promising." And pentosan polysulfate is not currently approved by the U.S. Food and Drug Administration for use in horses.

The regenerative therapies interleukin-1 receptor antagonist protein (IRAP), platelet-rich plasma (PRP), and stem cells also appear beneficial for OA treatment in horses. Veterinarians are currently using IRAP and PRP to treat horses with OA, but not all veterinarians offer these services, and research is ongoing.

In this article we'll look at some of the products scientists are studying that either already are or might prove useful as disease-modifying therapies. It is also possible that one of these therapies might ultimately prove to be the OA "cure" for which horse owners hope.

Nutritional Supplements

Physicians often recommend a multimodal approach to medically managing human OA. This approach includes both nonpharmacologic modalities (e.g., weight management, physical therapy) and drug therapy. Several reports have described the important role of oral joint health supplements (OJHS) in human OA management.

In equine medicine, however, the pool of data regarding OJHS efficacy is lmited. Thus, it can be challenging to make clear and fast evidence-based recommendations regarding OJHS use for OA.

So far scientists have proven only one OJHS to be a disease-modifying treatment for managing equine OA medically: ASU. Other nutritional supplements have not been tested using the same (or a similar) model of OA in live horses. Thus, even though some other OJHS ingredients might ultimately prove to be disease-modifying, currently there is not enough scientific proof to support this hypothesis.

Treating Osteoarthritis at the Molecular Level

"Go small or go home" appears to be the new catch phrase at the Ohio State University's Comparative Orthopedic Laboratory, at which researchers are studying a novel molecular approach to finding the cure for osteoarthritis (OA) in horses that equine industries the world over have been searching for.

"Osteoarthritis remains a major problem in horses," explains Alicia L. Bertone, DVM, PhD, Dipl. ACVS, the Trueman Family Endowed Chair and Professor in Equine Orthopedic Surgery at The Ohio State University. "To date, ways to regenerate cartilage rather than simply reduce inflammation and control pain in affected horses remains to be discovered."

Nutritional supplements and regenerative therapies (such as stem cells and platelet-rich plasma) are currently available and are increasingly popular options for treating OA; however, neither has "proven" itself via an evidence-based medicine approach.

An alternative approach to treating OA is to address the problem at the genetic level.

Colorado State University researchers are already looking at gene therapy for increasing the production of interleukin-1 receptor antagonist protein (IRAP) to stop OA.

According to Bertone, "Another possible cure for OA is to interfere with the genetic material to stop proteins that break down cartilage, like IL-1, from being produced. This technique, which is called 'RNA inhibition' is currently being explored in human medicine as well, most notably to treat patients with liver cancer."

RNA inhibition uses small interfering ribonucleic acid units that are specifically designed to bind to an important gene product to stop that gene from being expressed.

Although this technique remains extremely experimental and has not been attempted in live horses, preliminary data in the laboratory using equine cartilage cell cultures is extremely promising, as described in the study, "Evaluation of the ability of two transfection reagents to deliver small interfering RNA molecules to equine and guinea pig cartilage in vitro" published in the June 2011 edition of the American Journal of Veterinary Research. Additionally, researchers have identified RNAi sequences that block IL-1 in cartilage in guinea pigs with OA, which will be published in Osteoarthritis & Cartilage later this year.

--Stacey Oke, MSc

Sulfated Glycosaminoglycans

Cells called chondrocytes make up normal, healthy articular cartilage; these chondrocytes produce the surrounding cartilage "matrix," which is responsible for absorbing shock during weight bearing. Sulfated glycosaminoglycans are one of the molecules found in the matrix.

In the United States only one sulfated glycosaminoglycan product is licensed for treating OA in horses: polysulfated glycosaminoglycan (Adequan). This product is licensed for both intramuscular (IM) and intra-articular (IA) administration; however, studies performed by McIlwraith et al. using the Colorado State University model of equine OA mentioned earlier (with the ASU study) indicate that only the IA route is disease-modifying for OA.

Another sulfated glycosaminoglycan product that has been studied using the Colorado State University model of OA is called pentosan polysulfate (PPS). As mentioned earlier, this product is not currently available in the United States, but it is used in OA-affected horses in other countries. In Australia the product is called Cartrophen Equine Forte, and it is marketed as a disease-modifying drug for OA.

"I found that horses treated with IM Cartrophen had beneficial effects on both grossly visible and microscopic characteristics," says McIlwraith. "These changes included a significant decrease in articular cartilage fibrillation (the softening and grooving of joint surface cartilage) and a significant decrease in the abnormal thickening of the lining of the joint that occurs in diseased joints. Together, these findings imply superiority of intramuscular PPS over intramuscular Adequan for OA."

According to McIlwraith, these PPS test results were promising, but the virtues of PPS should not be overstated.

"Owners should note that PPS did not significantly improve lameness and range of motion," he clarifies. "It merely had positive effects in articular cartilage fibrillation, which implies it is truly disease-modifying with no change in symptoms."

Regenerative Medicine

As discussed in detail in The Horse's June 2011 Sports Medicine article, some evidence also exists that stem cells, PRP, and IRAP might be disease-modifying therapies for horses with OA.

"Using the Colorado State University model for OA, we demonstrated that IRAP does have a beneficial effect on OA, presumably by blocking the production of the harmful pro-inflammatory molecule interleukin-1 in the joint environment," relays McIlwraith.

Like IRAP, PRP is currently being used in horses with OA; however, no full-length, peer-reviewed studies using horses with either naturally occurring OA or an OA model have been published.

Gene Therapy

Gene therapy is the insertion, alteration, or removal of genes within an individual's cells or biological tissues to treat disease. Researchers use virus shells as vectors to deliver genetic material to horse cells, using viruses that don't infect/cause equine disease. In horses, researchers have started looking at the potential use of gene therapy in OA by targeting interleukin-1.

Initially, McIlwraith and colleagues identified the genetic sequence for the interleukin-1 receptor antagonist protein. They then packaged the genetic sequence inside an adenovirus (a virus to be used as a vector that cannot actually infect the horse), before injecting it into the affected joint of horses with OA. The viruses infected various cells such as chondrocytes or the cells in the joint lining (synoviocytes). Once infected, these cells began producing larger-than-normal quantities of IRAP. Just like with the IRAP system described above in the regenerative medicine section, the IRAP produced from gene therapy inhibited the pro-inflammatory molecule interleukin-1's activity in the joint.

"Dr. David Frisbie (DVM, PhD, Dipl. ACVS) and our group demonstrated efficacy with gene therapy using IL-1Ra with an adenoviral vector," explains McIlwraith.

Specifically, after injecting the virus containing the equine IL-1Ra gene into horses' knee joints, the cells lining the joint produced increased amounts of the IL-1Ra protein within 48 hours of treatment. The research team also found that cells produced the IL-1Ra for 28 days after injection.

In an ensuing study Frisbie et al. injected the virus containing the equine IL-1Ra gene into one knee joint in each of eight horses. Eight additional horses received no treatment and served as the control group. Fifty-six days after treatment researchers noted a significant improvement in lameness and pain in the treated horses, as well as a decrease in synovitis (inflammation of the membrane that lines joints) and complete prevention of articular cartilage degradation.

McIlwraith adds, "This study shows the most impressive results in the CSU OA model of any product tested to date."

Presently, the research team is looking at ways to improve or maximize IRAP gene delivery into the cells in the joint.

Laurie Goodrich, DVM, PhD, Dipl. ACVS, an assistant professor in equine lameness and surgery, also from CSU, explains, "We are currently testing a different type of adenovirus called an adeno-associated virus (AAV) to assess the ability for this virus to deliver the IRAP gene. The results are very promising. To date we have completed a pilot test in two horses, but plan to continue safety and efficacy testing this year. We already have funding from the National Institutes of Health and Grayson-Jockey Club (Research) Foundation to execute these studies."

"We are hopeful that the AAV vector that Laurie Goodrich is working will be as successful as the initial adenovirus we developed," adds McIlwraith.

Some of the challenges inherent in gene therapy are:

The gene needs to be delivered to the joint without inducing an immune response to the virus; and

The gene needs to produce a high enough concentration of IRAP in the joint to inhibit interleukin-1 for a sufficiently long period of time;

As straightforward as the process seems in theory, it is anything but easy in real life. In fact, gene therapy has been discussed for nearly 20 years already. But despite the apparent slow progress, this therapy is promising.

Miscellaneous Theories and Hypotheses

Two additional noteworthy treatment options, namely nitric oxide and tissue engineering, also are in various stages of development.

Nitric OxideLike interleukin-1, nitric oxide (NO) is one of the "bad boys" in OA. Interleukin-1 and other pro-inflammatory mediators (cytokines) stimulate various cell types' NO production in the joint. The increased NO production inhibits cartilage matrix synthesis and, ultimately, the cartilage degrades. Further, NO reacts with free radicals in the joint that are formed during metabolism and can damage other cells and cell structures. In human medicine some researchers are trying to find ways to inhibit NO production (by blocking an enzyme called nitric oxide synthase).

Tissue EngineeringTissue engineering is part of the regenerative medicine field focused on developing biological substitutes that restore, maintain, or improve tissue function or even a whole organ.

Goodrich and colleagues have conducted one study so far using bone marrow derived stem cells mixed with a fibrin (a protein normally found in the blood and the primary component of blood clots) "glue" that is PRP-enhanced. They then tested this "tissue" in a cartilage defect model to assess the engineered tissue's impact on cartilage healing.

"We anticipate having the results from this pilot study by the year's end," predicts Goodrich. "If this technique improves the cartilage defect healing process, then this could potentially be an excellent way to improve cartilage repair early on in the disease process. Thus, the outcome of devastating osteoarthritis that typically follows after cartilage is injured and cartilage defects occur could be avoided."

Take-Home Message

Treating OA-afflicted horses to control the resulting pain, swelling, and decreased range of motion can be a laborious and frustrating process for horse owners. Nonetheless, researchers are making exciting progress in this field. Rest assured they are not idling in their quest for finding a cure for OA.

About the Author

Stacey Oke, MSc, DVM, is a practicing veterinarian and freelance medical writer and editor. She is interested in both large and small animals, as well as complementary and alternative medicine. Since 2005, she's worked as a research consultant for nutritional supplement companies, assisted physicians and veterinarians in publishing research articles and textbooks, and written for a number of educational magazines and websites.

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